Integration of Upstream and Downstream in Continuous Biomanufacturing

Gronemeyer, Petra; Thiess, Holger; Zobel-Roos, Steffen; Ditz, Reinhard; Strube, Jochen

doi:10.1002/9783527699902.ch17

Cited by 12 publications

(18 citation statements)

References 110 publications

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“…The separation sequence could be designed in silico a priori by various simulation studies which show the purification power of each step as quantified feed input of the next one. The benefits of appropriate USP and DSP integration have been demonstrated before [12,13,106,119]. Besides, USP modeling with Monod kinetics including reduced metabolomics [52,[120][121][122][123] enable to integrate USP into total process design as well as lyophilization as the final steps towards formulation [116][117][118].…”

Section: Industrializationmentioning

confidence: 99%

“…Biologics currently contribute more than 30% to the pharmaceutical drug market with attractive growth rates [1][2][3][4][5][6][7][8][9]. Monoclonal antibodies (mAb) contribute now approximately 70% of the biologics market [4], with a platform technology based, yet improvable production process [10][11][12][13]. Moreover, market analysis of company pipelines and drug substances in the approval process with regulatory authorities such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) indicates that a broader variety of novel therapies are moving forward to cope with urging societal needs, e.g., oncology or diabetes, cell therapy, virus-like particles (VLP), exosomes, Methicillin-resistant Staphylococcus aureus (MRSA) antibiotics and diabetes cures.…”

Section: Introductionmentioning

confidence: 99%

“…Single-use/disposable technology seems to be a temporary intermediate step towards efficient in-house processes, but the sustainability of a few thousand kilograms of solid waste disposal vs. buffer cleaning costs is questionable in the long run. Proper balancing of the whole value chain seems to be necessary to avoid erroneous investments [10][11][12]34].…”

Section: Introductionmentioning

confidence: 99%

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Accelerating Biologics Manufacturing by Modeling or: Is Approval under the QbD and PAT Approaches Demanded by Authorities Acceptable without a Digital-Twin?

et al. 2019

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Innovative biologics, including cell therapeutics, virus-like particles, exosomes,recombinant proteins, and peptides, seem likely to substitute monoclonal antibodies as the maintherapeutic entities in manufacturing over the next decades. This molecular variety causes agrowing need for a general change of methods as well as mindset in the process development stage,as there are no platform processes available such as those for monoclonal antibodies. Moreover,market competitiveness demands hyper-intensified processes, including accelerated decisionstoward batch or continuous operation of dedicated modular plant concepts. This indicates gaps inprocess comprehension, when operation windows need to be run at the edges of optimization. Inthis editorial, the authors review and assess potential methods and begin discussing possiblesolutions throughout the workflow, from process development through piloting to manufacturingoperation from their point of view and experience. Especially, the state-of-the-art for modeling inred biotechnology is assessed, clarifying differences and applications of statistical, rigorousphysical-chemical based models as well as cost modeling. “Digital-twins” are described and effortsvs. benefits for new applications exemplified, including the regulation-demanded QbD (quality bydesign) and PAT (process analytical technology) approaches towards digitalization or industry 4.0based on advanced process control strategies. Finally, an analysis of the obstacles and possiblesolutions for any successful and efficient industrialization of innovative methods from processdevelopment, through piloting to manufacturing, results in some recommendations. A centralquestion therefore requires attention: Considering that QbD and PAT have been required byauthorities since 2004, can any biologic manufacturing process be approved by the regulatoryagencies without being modeled by a “digital-twin” as part of the filing documentation?

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Section: Industrializationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Accelerating Biologics Manufacturing by Modeling or: Is Approval under the QbD and PAT Approaches Demanded by Authorities Acceptable without a Digital-Twin?

et al. 2019

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“…However, with higher product concentrations the platform downstream process will reach its efficiency optimum. Increasing the product concentration even more leads to a significant shift of cost of goods (COGs) from upstream to downstream processing [4,[19][20][21].…”

Section: Critical View On Current Practicementioning

confidence: 99%

“…Continuous bioprocessing circumvents the aforementioned downstream bottleneck and batch scale-up problems by increasing the productivity and flexibility of each unit operation with a simultaneous increase in product quality resulting from continuous product processing (i.e., short hold times) [6,14,[21][22][23][24][25][26][27][28][29][30][31][32][33]. The FDA (U.S. Food and Drug Administration), EMA (European Medicinal Agency), ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), and various industrial working groups have started to publish guidelines (ICH Q8 to Q11) to increase product quality during manufacturing and; therefore, promoting continuous bioprocessing [34][35][36][37][38][39].…”

Section: Critical View On Current Practicementioning

confidence: 99%

Accelerating Biomanufacturing by Modeling of Continuous Bioprocessing—Piloting Case Study of Monoclonal Antibody Manufacturing

et al. 2019

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An experimental feasibility study on continuous bioprocessing in pilot-scale of 1 L/day cell supernatant, that is, about 150 g/year product (monoclonal antibody) based on CHO (Chinese hamster ovary) cells for model validation is performed for about six weeks including preparation, start-up, batch, and continuous steady-state operation for at least two weeks stable operation as well as final analysis of purity and yield. A mean product concentration of around 0.4 g/L at cell densities of 25 × 106 cells/mL was achieved. After perfusion cultivation with alternating tangential flow filtration (ATF), an aqueous two-phase extraction (ATPE) followed by ultra-/diafiltration (UF/DF) towards a final integrated counter-current chromatography (iCCC) purification with an ion exchange (IEX) and a hydrophobic interaction (HIC) column prior to lyophilization were successfully operated. In accordance to prior studies, continuous operation is stable and feasible. Efforts of broadly-qualified operation personal as well as the need for an appropriate measurement and process control strategy is shown evidently.

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